Survivors of myocardial infarction (MI) remain at high risk for cardiac arrhythmias and sudden cardiac death. The infarct, or scar, generates an anatomical substrate for the initiation of re-entrant arrhythmias and numerous studies indicate that altered sympathetic neurotransmission in the region of the scar plays a key role in the onset of these untoward post-infarct events. The transmural (epicardial to endocardial) gradient in action potential duration (APD), which is accompanied by a transmural gradient in sympathetic innervation density, is critical for normal activation and repolarization of the left ventricle. Norepinephrine (NE) released from sympathetic nerves activates cardiac β-adrenergic receptors (β-AR) to modulate the rate of myocyte repolarization by altering Ca2+ homeostasis, and simply disrupting the transmural gradient of sympathetic innervation in an otherwise normal heart is arrhythmogenic.
Cardiac sympathetic function is altered in a region-specific manner following MI, and studies in animals and humans reveal denervation of the infarct and adjacent viable (peri-infarct) myocardium. Three recent studies in patients with implanted cardioverter defibrillators (ICDs) suggest that the amount of sympathetic denervation after MI predicts the probability of serious ventricular arrhythmias. Furthermore, a detailed electrical mapping study in intact human hearts revealed that sympathetic denervation of the normal myocardium adjacent to the scar resulted in β-AR agonist supersensitivity and increased dispersion of repolarization that as arrhythmogenic.